5,6-diphenyl-1,2,4-triazinic dimeric derivatives and the use thereof in the form of sun-protective agents

ABSTRACT

The invention relates to 5,6-diphenyl-1,2,4-triazinic compounds of general formula (I), wherein identical or different R1, R2, R3 and R4 represent a hydrogen, fluoride, chloride or bromine atom, C1 to C12 linear or branched alkyl, C1 A C18 linear or branched hydroxy, alkoxy poly(ethoxy)-alkoxy with a C1 to C4 alkyl fragment and an ethoxy number ranging from 1 to 4, amino or mono or di-alkylamino with a C1 to C4 alkyl fragment group, X is ortho-, meta- or paraphenylene, 4,4′-biphenylene, 2,4- or 2,6- or 3,4- or 3,5-pyridinylene, 2,2′-bipyridinylene, meta- or paraphenylenediamino, ethylenediamine, 2,2′-piperazinylene, diacyl of formula -(R4CO)2-, wherein r represents a phenyl radical, a 3 to 10 carbon, phenanthrene or anthracene atoms alkyl chain except 1,4-bis(5,6-diphenyl-1,2,4-triazin-3-yl)benzene of 2,4-bis(5,6-diphenyl-1,2,4-triazin-3-yl)pyridine and of 2,6-bis(5,6-diphenyl-1,2,4-triazin-3-yl)pyridine, to cosmetic compositions containing said compounds and to the use thereof in the form of sun filters or light-protective agents.

The present invention relates to 5,6-diphenyl-1,2,4-triazinederivatives, and in particular to the use thereof as sun filters onhuman skin and hair or as light-protective agents in the syntheticmaterials industry such as plastics, glass and textiles. The presentinvention also has as an object cosmetic compositions containing theaforesaid derivatives.

As a brief review, the action of solar radiation on the skin dependsprimarily on the energy of the radiation which reaches the variouscutaneous layers. Generally speaking, the most energetic radiation,i.e., having the shortest wavelength (E=hc/λ), cause erythemas or“sunburn”, whereas less energetic radiation only causes a simplebrowning of the skin. It is thus considered that a sun filter intendedto be part of the composition of so-called “sunscreen” cosmeticpreparations must absorb short wavelength radiation to the maximumdegree possible while remaining transparent to radiation of longerwavelength.

Photobiologists typically divide the ultraviolet spectrum into threeparts, called UV-A, UV-B and UV-C, which correspond to the decreasingwavelength ranges from 400 nm to 320 nm, from 320 nm to 280 nm and from280 nm to 200 nm, respectively.

UV-B and UV-A allow the tanning of the human epidermis. UV-B causeserythemas and cutaneous burns which can harm the development of anatural tan. For these reasons, as well as for esthetic reasons, aconstant demand exists for methods of controlling this natural tanningwith a view to controlling the color of the skin. It is thus advisableto filter this UV-B radiation.

It is also known that UV-A rays are likely to induce a deterioration ofthe skin, in particular in the case of sensitive skin or skincontinuously exposed to sun radiation. In particular, UV-A rays cause aloss of skin elasticity and the appearance of wrinkles which lead topremature aging. They cause the triggering of the erythematous reactionor amplify this reaction in certain subjects and can even be the causeof phototoxic or photoallergic reactions. It is thus desirable to UVfilter-A radiation as well.

UV-C, which is the most highly energetic, causes photokeratitis. Theozone formed in the stratosphere generally absorbs a large part of thisUV-C radiation which, on the other hand, is found in large amounts inthe radiation emitted by artificial lamps, which are often responsiblefor serious cutaneous injuries. UV-B, which penetrates the skin layerand, in particular, the stratum mucosum of the epidermis, causes solarerythemas. Consequently, UV-B and UV-C radiation together constitute theso-called erythema spectrum with regard to which sun filters must act asa screen. UV-A produces the direct pigmentation of the skin(melanogenesis), i.e., the tanning of the skin.

Compounds derived from the benzotriazoles and/or the benzotriazoles areknown as UV filters, in particular in the field of cosmetics. The patentapplication FR 2,803,194 thus disclosed S-triazine derivatives carryingphenylbenzothiazole or benzothiazole groups useful as UV filters inparticulate form. These compounds cover the range of UV-A and of UV-Bbut they exhibit the major disadvantage of absorbing in the visiblespectrum (wavelengths longer than 400 nm). Thus these products areheavily colored, which limits their use in cosmetic products.

The present invention proposes novel 5,6-diphenyl-1,2,4-triazinederivatives capable of absorbing in UV-A and/or UV-B and/or UV-C,without absorbing in the visible spectrum. Thus these compounds have theadvantage of being lightly colored.

They also have the advantage of being capable of being specific to oneof these spectra. This is advantageous when it is desired to filter aspecific UV spectra (UV-A, UV-B or UV-C), for example to supplement thespectral effectiveness of a UV filter which exhibits a gap in thisspecific range.

These novel derivatives thus offer a varied range of specific UV filterswhich can also exhibit various degrees of absorbance. The combination ofseveral of these filters selected according to their specificity andtheir degree of absorbance thus makes it possible to prepare all typesof UV filters acting in the spectrum and with the absorbance desired.

These novel derivatives also have the advantage of being soluble invarious pharmaceutically acceptable excipients and of exhibiting betterphotostability than certain commercial filters, which makes themparticularly useful in cosmetic products, notably in sun protectors.

The present invention has as an object the 5,6-diphenyl-1,2,4-triaziniccompounds of general formula (I):

wherein:

-   -   R₁, R₂, R₃ and R₄, identical or different, represent a hydrogen,        fluorine, chlorine or bromine atom, a C₁ to C₁₂ linear or        branched alkyl group, a hydroxy group, a C₁ to C₁₈ linear or        branched alkoxy group, a poly(ethoxy)-alkoxy group with a C₁ to        C₄ alkyl fragment and an ethoxy number ranging from 1 to 4, an        amino group, or a mono- or di-alkylamino group with a C₁ to C₄        alkyl fragment,    -   X represents an ortho-, meta- or para-phenylene group, a        4,4′-biphenylene group, a 2,4- or 2,6- or 3,4- or        3,5-pyridinylene group, a 2,2′-bipyridinylene group, a meta- or        para-phenylenediamino group, an ethylenediamino group, a        2,2′-piperazinylene group, a diacyl group of formula —(R₄CO)₂—        wherein R₄ represents a phenyl radical, an alkylated chain of 3        to 10 carbon atoms, phenanthrene or anthracene, with the        exception of 1,4-bis(5,6-diphenyl-1,2,4-triazin-3-yl)benzene        (X=para-phenylene; R₁, R₂, R₃, R₄=—H),        2,4-bis(5,6-diphenyl-1,2,4-triazin-3-yl)pyridine, and        2,6-bis(5,6-diphenyl-1,2,4-triazin-3-yl)pyridine.

Among the compounds of general formula (I), the following compounds haveled to particularly advantageous practical results:

-   -   R₁, R₂, R₃ and R₄ represent a C₁ to C₁₂ linear or branched alkyl        group located in the para position, or a C₁ to C₁₈ linear or        branched alkoxy group located in the para position, and    -   X represents a 4,4′-biphenylene group.

The present invention also has as an object cosmetic sunscreencompositions containing an effective quantity of at least one compoundof formula (I) in combination with a cosmetically acceptable excipient,preferably between 0.1% and 20% by weight with respect to the totalweight of the composition.

The cosmetic sunscreen compositions according to the invention maycontain in addition one or more sun filters active in UV-A and/or UV-Band/or UV-C (absorbers), either hydrophilic or lipophilic. Theseadditional filters may be selected among, in particular, cinnamicderivatives, dibenzoylmethane derivatives, salicylic derivatives,camphor derivatives and triazine derivatives other than those previouslycited in the present invention.

The present invention also has as an object the use, as sun filtersactive in UV-A and/or UV-B and/or UV-C for human skin and/or hair, of5,6-diphenyl-1,2,4-triazinic compounds of general formula (I):

wherein:

-   -   R₁, R₂, R₃ and R₄, identical or different, represent a hydrogen,        fluorine, chlorine or bromine atom, a C₁ to C₁₂ linear or        branched alkyl group, a hydroxy group, a C₁ to C₁₈ linear or        branched alkoxy group, a poly(ethoxy)-alkoxy group with a C₁ to        C₄ alkyl fragment and an ethoxy number ranging from 1 to 4, an        amino group, or a mono- or di-alkylamino group with a C₁ to C₄        alkyl fragment,    -   X represents an ortho-, meta- or para-phenylene group, a        4,4′-biphenylene group, a 2,4- or 2,6- or 3,4- or        3,5-pyridinylene group, a 2,2′-bipyridinylene group, a meta- or        para-phenylenediamino group, an ethylenediamino group, a        2,2′-piperazinylene group, a diacyl group of formula —(R₄CO)₂—        wherein R₄ represents a phenyl radical, an alkylated chain of 3        to 10 carbon atoms, phenanthrene or anthracene.

The present invention also has as an object the use of compounds such aspreviously defined as light-protective agents active in the UV-A and/orUV-B and/or UV-C spectra, useful in the synthetic materials industry, inparticular as light-protective agents incorporated into the compositionof plastics, glass or textiles.

These compounds, which are objects of the present invention, can thus beused to protect photosensitive materials.

The light-protective agent could be incorporated into a substratum withthe goal of protecting said substratum against attack from ultravioletrays, to prevent the modification of one or several physical propertiesof said substratum, such as, for example, discoloration, a change inresistance to tearing, an increase in brittleness, etc., and/or toprevent chemical reactions caused by ultraviolet rays, for example theoxidation process. In this case, the protective agent can beincorporated before and during the preparation of the substratum, or ata later time by a suitable process, for example a binding processanalogous to dyeing.

The light-protective agent can also be incorporated into a substratum toprotect one or more additional substances incorporated into theaforesaid substratum, for example dyes, auxiliary agents, etc.

The light-protective agent can also be incorporated into a filter layerthat may be a solid (film, sheet) or semi-solid (cream, oil, wax)applied to a substratum for the purpose of protecting said substratumfrom ultraviolet rays.

The compounds of the present invention are suitable not only aslight-protective agents for colorless materials, but also for pigmentedmaterials. In this case, the protection against light is extended to thecoloring agents, thus allowing in many cases a quite notable improvementof stability in light.

The compounds of general formula (I) can be prepared from 1,2-diketonesof formula (II), by conventional methods known to those skilled in theart, such as those described in the examples which follow.

in which R₁ and R₂ have the same significance as that given previously.

The diketones of formula (II) are available commercially (such as, forexample, benzyl(diphenylethan-1,2-dione), 4,4′-dimethylbenzyl,4,4′-dibromobenzyl, 4,4′-difluorobenzyl or 4,4′-dichlorobenzyl) or canbe synthesized by conventional methods well known to those skilled inthe art. For example, the following synthesis route can be used:

The examples which follow give other examples of syntheses of diketonesof formula (II).

The present invention will be illustrated below by mentioning severalnonrestrictive examples of the preparation of representative derivativesconforming to general formula (I).

The compounds prepared are summarized in table 1.

TABLE 1 (I)

(wherein R₁, R₂, R₃ and R₄ are in the para position) Reference X R₁, R₂,R₃, R₄ WP30 

H WP35 

OH WP38 

Me—(CH₂)₁₇—O— WP39 

Me WP40 

MeO— WP41 

MeO—(OCH₂—CH₂)₄— WP52 

Br WP89 

F WP96 

Me—(CH₂)₅— WP100

Cl WP104

tert-Bu WP107

Me—(CH₂)₁₁— WP144

Me—(CH₂)₃—CH(Et)—CH₂—O— WP149

Me—(CH₂)₅—CH(Me)—O— WP151

Me—CH(Me)—(CH₂)₂—CH(Me)₂— WP135

—H WP76 

—H

The compounds of formula (I) of table 1 can be synthesized in thefollowing way:

wherein R1, R2=hydrogen, halogen,

-   -   —OH,    -   C₁ to C₁₈ linear or branched alkoxy (such as —OMe),    -   C₁ to C₁₂ linear or branched alkyl,    -   mono- or di-alkylamino with a C₁ to C₄ alkyl fragment (such as        —N(Et)₂).

FIGURES

DMB=Parsol 1798® (Roche Laboratories)

MCX=Parsol MCX® (Roche Laboratories)

FIG. 1 represents the UV-A and UV-B absorption spectra of compoundsWP89, WP96, WP100, WP104, WP107, WP135, WP144, WP149 and WP151.

FIG. 2 represents the UV-A and UV-B absorption spectra of compoundsWP35, WP39, WP41, WP52 and WP30.

FIG. 3 represents the UV-A and UV-B absorption spectra of compound WP76.

EXAMPLE 1 Synthesis of 1,2-bis(4-methoxyphenyl)-ethane-1,2-dione⁽¹⁾

Oxalyl chloride (4.71 ml, 55.2 mmol) at 0° C. is slowly added to amixture of anisole (10.8 g, 100 mmol) and aluminum chloride (33.33 g,250 mmol). The mixture is stirred at ambient temperature for 4 hours.After cooling, it is poured into iced water and extracted withdichloromethane. The organic phases collected are washed with 2 N HClthen with brine and are dried on magnesium sulfate. After filtration andconcentration under reduced pressure, the residue is recrystallized inethanol. The resulting precipitate is filtered, washed several times inethanol and dried to yield 9.80 g (66%) of pure product in the form of ayellow solid. δ_(H) (200 MHz, CDCl₃) 3.93 (s; 6H), 6.99 (d; J 7.8; 4H),7.99 (d; J 7.8; 4H).

EXAMPLE 2 Synthesis of Diethyl Terephthalimidate⁽²⁾ (WP18)

A suspension of terephthalonitrile (12.81 g, 100 mmol) in absoluteethanol (250 ml) cooled to 0° C. is bubbled with HCl gas for 18 hours,during which the temperature rises to ambient temperature. The whitesolid obtained (27.5 g of dichlorohydrate salt) is then filtered andwashed with ethanol. The neutralization of this salt, dissolved in aminimum of water at 0° C., is carried out by adding a potash solution(15% aqueous) up to basic pH. A white solid is obtained (yield>90%)after filtration, successive washes with water then with pentane anddrying. mp 158-161° C.; δ_(H) (300 MHz, CDCl₃) 1.43 (t; J 7.2; 6H), 4.32(q; J 7.2; 4H), 7.79 (s; 4H); SM (Electrospray) m/z 222 (40%), 221 (MH⁺,100%), 193 (M-CH═CH₂, 42%).

EXAMPLE 3 Synthesis of Terephthalamidrazone⁽²⁾ (WP29)

Hydrazine monohydrate (6.55 ml; 135 mmol) is added over the course of 10minutes to a suspension of WP18 prepared according to example 2 (9.92 g,45.035 mmol) in absolute ethanol (75 ml). The mixture quickly becomeshomogeneous, then a yellow precipitate slowly forms. After 24 hours, theprecipitate is filtered, washed successively with ethanol then withdiethyl ether and is dried to yield 6.838 g (79%) of a yellow solid.δ_(H) (300 MHz, D₂0) 7.66 (s; 4H).

EXAMPLE 4 Synthesis of1,4-bis(5,6-diphenyl-1,2,4-triazin-3-yl)benzene⁽³⁾ (WP30)

Terephthalamidrazone WP29 prepared according to example 3 (1.00 g, 5.203mmol) is added all at once to a solution of benzyl (2.455 g, 11.67 mmol)in ethanol (100 ml). The mixture is heated at reflux for 15 hours. Afterreturning to ambient temperature, the precipitate obtained is filtered,washed successively with ethanol then with diethyl ether and is dried toyield 2.587 g (92%) of a yellow solid. mp=321° C.; δ_(H) (300 MHz,DMSO-d, 120° C.) 7.42-7.52 (m; 12H), 7.62 (m; 4H), 7.71 (m; 4H), 8.81(s; 4H); δ_(C) (75 MHz, DMSO-d, 120° C.) 129.2 (1), 129.3 (1), 130.2(1), 130.3 (1), 130.5 (1), 131.4 (1), 136.5 (0), 136.6 (0), 138.4 (0),156.5 (0), 156.9 (0), 161.3 (0); MS (Nanospray) m/z 1081 (2M+H⁺, 22%),541 (MH⁺, 41%).

EXAMPLE 5 Synthesis of 4,4′-dihydroxybenzyl⁽⁴⁾ (WP32)

A mixture of 1,2-bis(4-methoxyphenyl)-ethane-1,2-dione preparedaccording to example 1 (7.275 g, 26.91 mmol) and pyridine hydrochlorate(15.55 g, 134.5 mmol) under an atmosphere of nitrogen is heated to 180°C. for 2 days. After returning to ambient temperature, the mixture isdiluted with ethyl acetate and water. The aqueous phase is extractedwith ethyl acetate and the recombined organic phases are dried onmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue is purified by flash chromatography on a silica gel (petroleumether/ethyl acetate 10/1 to 2/1) to yield 5.789 g (89%) of a whitesolid. δ_(H) (300 MHz, MeOH-d) 6.91 (d; J 9.0; 4H), 7.82 (d; J 9.0; 4H).

EXAMPLE 6 p-Tosylate of2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethyl⁽⁵⁾ (WP33)

To a mixture of tetraethylene glycol monomethyl ether (3.00 g, 14.406mmol) and soda (0.865 g, 21.6 mmol) diluted in THF (33 ml) and water (4ml) cooled to 0° C., a solution of p-toluenesulfonic acid chloride(3.021 g, 15.8 mmol) in THF (4 ml) is slowly added. After 3 hours ofstirring at 0° C., the mixture is poured into iced water (10 ml) and isdiluted by dichloromethane. The aqueous phase is extracted withdichloromethane and the recombined organic phases are washed with waterthen with a NaCl-saturated solution, dried on MgSO₄, filtered andconcentrated under reduced pressure. The residue is purified by flashchromatography on a silica gel (petroleum ether/ethyl acetate 1/1 to1/4) to yield 4.234 g (82%) of a colorless oil. δ_(H) (300 MHz, CDCl₃)identical to the literature.

EXAMPLE 7 Synthesis of1,4-bis[5,6-(4,4′-dihydroxy)-diphenyl-1,2,4-triazin-3-yl]benzene (WP35)

To a solution of WP32 prepared according to example 5 (600 mg, 2.47mmol) in ethanol (20 ml), terephthalamidrazone WP29 prepared accordingto example 3 (190 mg, 0.991 mmol) is added all at once. The mixture isheated at reflux for 15 hours. After returning to ambient temperature,the precipitate obtained is filtered, successively washed with ethanolthen with diethyl ether and is dried to yield 479 mg (80%) of a yellowsolid. δ_(H) (300 MHz, DMSO-d, 25° C.) 6.79-6.84 (m; 8H), 7.44 (d; J8.4; 4H), 7.58 (d; J 8.4; 4H), 8.71 (s; 4H), 10.03 (sl; 4H); MS(Nanospray) m/z 605 (MH⁺, 53%)

EXAMPLE 8 Synthesis of1,2-bis-[4-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)phenyl]-ethane-1,2-dione(WP36)

1,2-bis(4-methoxyphenyl)-ethane-1,2-dione prepared according to example1 (1.135 g, 4.687 mmol) and then potassium carbonate (3.239 g, 23.4mmol) are added successively to a solution of tosylate WP33 preparedaccording to example 6 (3.737 g, 10.3 mmol) in DMF (50 ml). The mixtureis stirred at 50° C. for 4 hours. After returning to ambienttemperature, the mixture is poured into iced water and extracted severaltimes with ethyl acetate. The recombined organic phases are washedseveral times with a NaHCO₃— saturated solution, then with brine. Afterdrying on MgSO₄, filtration and concentration under reduced pressure,the residue obtained is purified by flash chromatography on a silica gel(ethyl acetate, then dichloromethane/methanol 1% to 1.5%) to yield 1.568g (54%, not optimized) of a yellow oil. δ_(H) (300 MHz, CDCl₃) 3.36 (s;6H), 3.51 (m; 4H), 3.51-3.71 (m; 20H), 3.87 (m; 4H), 4.19 (m; 4H), 6.97(d, J 8.8; 4H), 7.92 (d, J 8.8; 4H); MS (Electrospray) m/z 623 (MH⁺,100%).

EXAMPLE 9 Synthesis of1,2-bis-(4-octadecyloxy-phenyl)-ethane-1,2-dione⁽⁶⁾ (WP37)

Soda (726 mg, 18.1 mmol) is added to a solution of1,2-bis(4-methoxyphenyl)-ethane-1,2-dione prepared according to example1 (2.00 g, 8.25 mmol) in DMF (50 ml). The mixture is stirred for 5minutes at ambient temperature, then 1-iodooctadecane (9.4 g, 24.7 mmol)is added over the course of 1 minute. After 3 hours of stirring to 60°C., the mixture is cooled. The precipitate obtained is filtered, washedsuccessively with DMF then with ethanol and dried under a vacuum toyield 3.792 g (61%) of a white solid. mp 87° C.; δ_(H) (300 MHz, C₆D₆)0.90 (t; J 6.0; 6H), 1.18-1.42 (m; 60H), 1.51 (m; 4H), 3.46 (t; J 6.5;4H), 6.64 (d; J 9.0; 4H), 8.09 (d; J 9.0; 4H); MS (Electrospray) m/z1493 (2M+H⁺, 5%), 747 (MH⁺, 26%).

EXAMPLE 10 Synthesis of1,4-bis[5,6-(4,4′-di-octadecyloxy)-diphenyl-1,2,4-triazin-3-yl]benzene(WP38)

Terephthalamidrazone WP29 prepared according to example 3 (200 mg, 1.04mmol) in ethanol (20 ml) is added all at once to a solution of WP37prepared according to example 9 (1.71 g, 22.88 mmol). The mixture isheated at reflux for 15 hours. After returning to ambient temperature,the precipitate obtained is filtered and washed with ethanol, thenpurified by flash chromatography on a silica gel (toluene, thentoluene/methanol 1% to 2%) to yield 1.409 g (84%) of a yellow solid.δ_(H) (300 MHz, C₆D₆) 0.91 (m; 6H), 1.18-1.42 (m; 120H), 1.51 (m; 8H),3.60 (m; 8H), 6.75 (d; J 9.0; 4H), 6.81 (d; J 9.0; 4H), 7.71 (d; J 9.0;4H), 7.73 (d; J 9.0; 4H), 9.22 (s; 4H); MS (Electrospray) m/z 1615 (MH⁺,64%), 1614 (75%), 890 (100%).

EXAMPLE 11 Synthesis of1,4-bis[5,6-(4,4′-dimethyl)-diphenyl-1,2,4-triazin-3-yl]benzene (WP39)

Terephthalamidrazone WP29 prepared according to example 3 (1.50 g, 7.804mmol) is added all at once to a solution of 4,4′-dimethylbenzyl (4.091g, 17.16 mmol) in ethanol (140 ml). The mixture is heated at reflux for15 hours. After returning to ambient temperature, the precipitateobtained is filtered, washed successively in ethanol then with diethylether and is dried to yield 4.42 g (95%) of a yellow solid. δ_(H) (300MHz, DMSO-d, 120° C.) 2.50 (s; 12H), 7.27 (m; 8H), 7.52 (d; J 8.0; 4H),7.61 (d; J 8.0; 4H), 8.78 (s; 4H); MS (Nanospray) m/z 1789 (3M+H⁺, 65%),1193 (2M+H⁺, 57%), 597 (MH⁺, 49%).

EXAMPLE 12 Synthesis of1,4-bis[5,6-(4,4′-dimethoxy)-diphenyl-1,2,4-triazin-3-yl]benzene (WP40)

Terephthalamidrazone WP29 prepared according to example 3 (1.50 g, 7.804mmol) is added all at once to a solution of1,2-bis(4-methoxyphenyl)-ethane-1,2-dione prepared according to example1 (5.273 g, 19.5 mmol) in ethanol (140 ml). The mixture is heated atreflux for 30 hours. After returning to ambient temperature, theprecipitate obtained is filtered, washed successively with ethanol,dichloromethane and diethyl ether then dried to yield 4.087 g (80%) of ayellow solid. δ_(H) (300 MHz, DMSO-d, 120° C.) 3.86 (s; 12H), 7.02 (m;8H), 7.58 (d; J 7.8; 4H), 7.71 (d; J 8.7; 4H), 8.77 (s; 4H); MS(Nanospray) m/z 661 (MH⁺, 8%), 332 (55%).

EXAMPLE 13 Synthesis of1,4-bis[5,6-(4,4′-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-)-diphenyl-1,2,4-triazin-3-yl]benzene(WP41)

Terephthalamidrazone WP29 prepared according to example 3 (64 mg, 0.337mmol) is added all at once to a solution of WP36 prepared according toexample 8 (524 mg, 0.842 mmol) in ethanol (7 ml). The mixture is heatedat reflux for 30 hours. After returning to ambient temperature, thesolvent is concentrated under reduced pressure and the residue ispurified directly by flash chromatography on a silica gel (ethylacetate, then ethyl acetate/methanol 2% to 6%) to yield 350 mg (76%) ofa yellow solid. δ_(H) (300 MHz, CDCl₃) 3.37 (s; 12H), 3.54 (m; 8H),3.60-3.74 (m; 40H), 3.88 (m; 8H), 4.18 (m; 8H), 6.93 (m; 8H), 7.60 (d, J8.8; 4H), 7.92 (d, J 8.8; 4H); 8.82 (s; 4H); δ_(C) (75 MHz, CDCl₃) 58.9(3), 67.3 (2), 67.4 (2), 69.4 (2), 69.5 (2), 70.4 (2), 70.5 (2), 70.7(2), 71.8 (2), 114.5 (1), 114.6 (1), 128.0 (1), 128.1 (1), 128.4 (1),130.6 (1), 131.4 (1), 137.5 (1), 154.2 (0), 154.7 (0), 159.9 (0), 160.1(0), 160.9 (0); MS (Electrospray) m/z 1387 (M+Na⁺, 24%), 1366 (MH⁺,100%).

EXAMPLE 14 Synthesis of1,4-bis[5,6-(4,4′-dibromo)-diphenyl-1,2,4-triazin-3-yl]benzene (WP52)

Terephthalamidrazone WP29 prepared according to example 3 (200 mg, 1.040mmol) is added all at once to a solution of 4,4′-dibromobenzyl (1.149 g,3.12 mmol) in ethanol (20 ml). The mixture is heated at reflux for 15hours. After returning to ambient temperature, the precipitate obtainedis filtered, washed successively with ethanol, dichloromethane anddiethyl ether then dried to yield 757 mg (85%) of a yellow solid. <δ_(H)(300 MHz, DMSO-d, 120° C.) 7.56-7.69 (m; 8H), 7.80-7.88 (m; 8H), 8.80(s; 4H).

EXAMPLE 15 Synthesis of 4-bromododecanoylbenzene⁽⁷⁾ (WP59)

Dodecanoyl chloride (44.1 ml, 191.1 mmol) is slowly added to a mixtureof bromobenzene (60 g, 382.1 mmol) and aluminum chloride (30.57 g, 229.3mmol). The mixture is stirred at 50° C. for 1 hour. After cooling, themixture is poured into iced water and extracted with dichloromethane.The recombined organic phases are washed with 2 N HCl then with brineand are dried on magnesium sulfate. After filtration and concentrationunder reduced pressure, the residue is taken up in ethanol. Theresulting precipitate is filtered, washed several times in ethanol anddried to yield 36.9 g (57%, not optimized) of pure product in the formof a white solid (no recrystallization). Analyses identical to theliterature.

EXAMPLE 16 Synthesis of 4-bromododecylbenzene⁽⁷⁾ (WP60)

Hydrazine monohydrate (23.6 ml, 4.5 eq) and then potash (24.3 g, 4 eq)are added to a solution of WP59 prepared according to example 15 (36.5g, 108.87 mmol) in tri(ethylene glycol) (180 ml). The mixture is stirredat reflux for approximately 15 hours. After cooling, it is poured intowater, acidified with concentrated HCl, then extracted withdichloromethane. The organic phase is washed with water, dried onmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue is purified by flash chromatography on a silica gel (pentane100%) to yield 21.2 g (60%, not optimized) of a colorless oil. Analysesidentical to the literature.

EXAMPLE 17 Synthesis of Diethyl Isophthalimidate (WP73)

A suspension of isophthalonitrile (12.81 g, 100 mmol) in a mixture ofdry 1,4-dioxane (100 ml)/absolute ethanol (14.6 ml) cooled to 0° C. isbubbled with HCl gas for 48 hours, during which time the temperaturereturns to ambient temperature. After 4 additional days of stirring, thewhite solid obtained (approximately 28 grams of di-chlorohydrate salt)is filtered and washed with diethyl ether. The neutralization of thissalt placed in suspension in diethyl ether is carried out by slowlyadding potassium an aqueous carbonate solution (30% by weight) up tobasic pH. The organic phase is separated, dried on MgSO₄, filtered andconcentrated under reduced pressure to yield a white solid (yield>90%).δ_(H) (300 MHz, CDCl₃) 1.44 (t; J 6.9; 6H), 4.32 (q; J 6.9; 4H), 7.47(t; J 7.5; 1H), 7.86 (d; J 7.5; 2H), 8.16 (s; 1H); SM (Electrospray) m/z221 (MH⁺, 100%).

EXAMPLE 18 Synthesis of Isophthalamidrazone⁽⁸⁾ (WP75)

Hydrazine monohydrate (485 μl, 9.98 mmol) is added over the course of 10minutes to a suspension of diethyl isophthalimidate WP73 preparedaccording to example 17 (1.0 g, 4.53 mmol) in dry acetonitrile (18 ml)cooled to 0° C. After 48 hours of stirring, the precipitate formed isfiltered, washed with acetonitrile and dried to yield 630 mg (72%) of ayellow solid. δ_(H) (300 MHz, D₂O) 7.50 (t; J 7.3; 1H), 7.67 (d; J 7.3;2H), 7.80 (s; 1H); SM (in solution in D₂O) (EI) m/z 199 (100%).

EXAMPLE 19 Synthesis of 1,3-bis(5,6-diphenyl-1,2,4-triazin-3-yl)benzene(WP76)

WP75 prepared according to example 18 (620 mg, 3.225 mmol) is added allat once to a solution of benzyl (1.491 g, 7.09 mmol) in ethanol (60 ml).The mixture is heated at reflux for 20 hours. After returning to ambienttemperature, the precipitate obtained is filtered, washed successivelywith ethanol then with diethyl ether and is dried to yield 1.488 g (85%)of a yellow solid. δ_(H) (300 MHz, DMSO-d, 120° C.) 7.42-7.52 (m; 12H),7.61 (d; J 1.2; 4H), 7.63 (d; J 1.5; 4H), 7.90 (t; J 7.3; 1H), 8.81 (d;J 7.3; 2H), 9.77 (s; 1H); MS (Electrospray) m/z 1081 (2M+H⁺, 74%), 541(MH⁺, 100%), 175 (88%).

EXAMPLE 20 Synthesis of1,4-bis[5,6-(4,4′-difluoro)-diphenyl-1,2,4-triazin-3-yl]benzene (WP89)

Terephthalamidrazone WP29 prepared according to example 3 (200 mg, 1.040mmol) is added all at once to a solution of 4,4′-difluorobenzyl (769 mg,3.12 mmol) in ethanol (20 ml). The mixture is heated at reflux for 15hours. After returning to ambient temperature, the precipitate obtainedis filtered, washed successively with ethanol then with diethyl etherand is dried under a vacuum to yield 541 mg (85%) of a yellow solid.δ_(H) (300 MHz, DMSO-d, 120° C.) 7.56-7.69 (m; 8H), 7.80-7.88 (m; 8H),8.80 (s; 4H). MS (Electrospray) m/z 613 (MH⁺, 100%), 178 (34%).

EXAMPLE 21 Synthesis of 1,2-bis(4-hexylphenyl)-ethane-1,2-dione (WP94)

A solution of s-BuLi (1.3 M in cyclohexane, 5.4 ml, 7.02 mmol) is slowlyadded to a solution of 4-bromo-n-hexylbenzene (1.68 g, 7.02 mmol) in THF(9 ml) at −78° C. and under an atmosphere of nitrogen. After one hour ofstirring, the mixture is transferred using a cannula to a suspension of1,4-dimethylpiperazine-2,3-dione (450 mg, 3.166 mmol) in THF (11 ml)cooled to −40° C. After returning to ambient temperature, the mixture isstirred for 15 hours then treated with 5 ml of 2 N HCl. After dilutionwith dichloromethane and stirring, the organic phase is separated,washed with 2 N HCl then with water, and dried on magnesium sulfate.After filtration and concentration, the residue is purified by flashchromatography on a silica gel (pentane/ethyl acetate 100/0; 4/1; 3/1;2/1) to yield 820 mg (68%) of a yellow oil. δ_(H) (300 MHz, CDCl₃) 0.87(t; J 6.6; 6H), 1.20-1.40 (m; 12H), 1.50-1.70 (m; 4H), 2.67 (t; J 7.5;4H), 7.30 (d; J 8.4; 4H), 7.87 (d; J 8.4; 4H); MS (IC) m/z 379 (MH⁺,100%).

EXAMPLE 22 Synthesis of1,4-bis[5,6-(4,4′-dihexyl)-diphenyl-1,2,4-triazin-3-yl]benzene (WP96)

Terephthalamidrazone WP29 prepared according to example 3 (43 mg, 0.22mmol) is added all at once to a solution of WP94 prepared according toexample 21 (187 mg, 0.49 mmol) in ethanol (5 ml). The mixture is heatedat reflux for 15 hours. After returning to ambient temperature, theprecipitate obtained is filtered, washed with ethanol and dried to yield144 mg (74%) of a yellow solid. δ_(H) (300 MHz, CDCl₃) 0.88 (m; 12H),1.20-1.40 (m; 24H), 1.45-1.70 (m; 8H), 2.65 (t; J 7.8; 8H), 7.18 (m;8H), 7.57 (d; J 8.4; 4H), 7.65 (d; J 7.8; 4H); MS (Electrospray) m/z1754 (2M+H⁺, 33%), 877 (MH⁺, 100%).

EXAMPLE 23 Synthesis of1,4-bis[5,6-(4,4′-dichloro)-diphenyl-1,2,4-triazin-3-yl]benzene (WP100)

Terephthalamidrazone WP29 prepared according to example 3 (24 mg, 0.122mmol) is added all at once to a solution of 4,4′-chlorobenzyl (75 mg,0.27 mmol) in ethanol (3 ml). The mixture is heated at reflux for 15hours. After returning to ambient temperature, the precipitate obtainedis filtered, washed successively with ethanol then with diethyl etherand dried under a vacuum to yield a yellow solid (yield not calculated).δ_(H) (300 MHz, DMSO-d, 120° C.) 7.50-7.60 (m; 12H), 7.69 (d; J 8.4;4H), 8.81 (s; 4H).

EXAMPLE 24 Synthesis of 1,2-bis(4-tert-butyl-phenyl)-2-hydroxy-ethanone(WP101)

A solution of potassium cyanide (4.61 g, 70.89 mmol) in water (14 ml) isslowly added to a solution of 4-tert-butylbenzaldehyde (115 g, 708.9mmol) in a methanol (300 ml)/water (40 ml) mixture. The mixture isstirred at 90° C. for 40 hours. After cooling, the methanol isconcentrated under reduced pressure and the residue is taken up indichloromethane and water. After three extractions with dichloromethane,the recombined organic phases are dried on magnesium sulfate, filteredand concentrated under reduced pressure. Pentane (approximately 800 ml)is then added, and the resulting precipitate is filtered, washed severaltimes in pentane and dried to yield 55.23 g (49%, not optimized) of pureproduct in the form of a white solid. Analyses identical to theliterature.

EXAMPLE 25 1,2-bis(4-tert-butyl-phenyl)-ethane-1,2-dione (WP103)

A 15% solution by weight of Dess-Martin periodinane in dichloromethane(100 ml, approximately 46.29 mmol) is added over the course of 10minutes to a solution of WP101 cooled to 0° C. prepared according toexample 24 (12 g, 37.037 mmol) in dry dichloromethane (350 ml). Themixture is stirred overnight, then diluted with dichloromethane andtreated with a solution saturated with sodium hydrogen carbonate. After10 minutes of stirring, the organic phase is separated and the aqueousphase is extracted with dichloromethane. The recombined organic phasesare washed with a solution saturated with sodium chloride, filtered andconcentrated under reduced pressure. The residue obtained is purified byflash chromatography on a silica gel (pentane/dichloromethane 4/1 to1.5/1) to yield 10.78 g (90%) of a yellow oil which is solidified undera high vacuum. Analyses identical to the literature.

EXAMPLE 26 Synthesis of1,4-bis[5,6-(4,4′-4-di-tert-butyl)-diphenyl-1,2,4-triazin-3-yl]benzene(WP104)

Terephthalamidrazone WP29 prepared according to example 3 (2.924 g,15.217 mmol) is added all at once to a suspension of WP103 preparedaccording to example 25 (10.78 g, 33.47 mmol) in ethanol (250 ml). Themixture is heated at reflux for 15 hours. After returning to ambienttemperature, the precipitate obtained is filtered, washed with ethanoland dried to yield 10.56 g (93%) of a yellow solid. δ_(H) (300 MHz,CDCl₃) 1.35 (s; 36H), 7.42 (m; 8H), 7.63 (d; J 8.1; 4H), 7.71 (d; J 8.4;4H), 8.85 (s; 4H); MS (Electrospray) m/z 1789 (3M+H⁺, 65%), 1530 (2M+H⁺,71%), 765 (MH⁺, 100%).

EXAMPLE 27 Synthesis of 1,2-bis(4-dodecylphenyl)-ethane-1,2-dione⁽⁷⁾(WP105)

A solution of 4-bromo-dodecylbenzene WP60 prepared according to example16 (20.19 g, 62.065 mmol) in THF (80 ml) is slowly added to a solutionof 30 ml of dry THF and s-BuLi (1.3 M in cyclohexane, 47.7 ml, 62.065mmol) cooled to −78° C. and under a nitrogen atmosphere. After one hourof stirring, the mixture is transferred using a cannula to a suspensionof 1,4-dimethylpiperazine-2,3-dione (107 mg, 0.7539 mmol) in THF (2.7ml) cooled to −40° C. The mixture is stirred for 15 hours then treatedwith 2 N HCl. After dilution with dichloromethane and stirring, theorganic phase is separated, washed with 2 N HCl then with water, and isdried on magnesium sulfate. After filtration and concentration, theresidue is purified by flash chromatography on a silica gel(pentane/ethyl acetate 100/0; 10/1; 4/1; 3/1; 2/1) to yield 2.77 g (18%)of a yellow oil. Analyses identical to the literature.

EXAMPLE 28 Synthesis of1,4-bis[5,6-bis(4-dodecylphenyl)-1,2,4-triazine-3-yl]benzene (WP107)

Terephthalamidrazone WP29 prepared according to example 3 (275 mg, 1.431mmol) is added all at once to a solution of WP105 prepared according toexample 27 (1.649 g, 3.147 mmol) in ethanol (70 ml). The mixture isheated at reflux for 15 hours. After returning to ambient temperature,the precipitate obtained is filtered, washed with ethanol and dried toyield 1.38 g (80%) of a yellow solid. δ_(H) (300 MHz, CDCl₃) 0.87 (m;12H), 1.20-1.40 (m; 72H), 1.50-1.70 (m; 8H), 2.63 (t; J 7.5; 8H), 7.20(m; 8H), 7.57 (d; J 8.1; 4H), 7.65 (d; J 8.4; 4H); MS (Electrospray) m/z1213.9 (MH⁺, 100%).

EXAMPLE 29 Synthesis of biphenyl-4,4′-diethyldicarboximidate (WP129)

A suspension of terephthalonitrile (2.5 g, 12.24 mmol) in absoluteethanol (30 ml) cooled to 0° C. is bubbled with HCl gas for 24 hours,during which time the temperature returns to ambient temperature. Thewhite solid obtained is then filtered and washed with ethanol. Theneutralization of this salt dissolved in a minimum of water at 0° C. iscarried out by adding a solution of 0° C. K₂CO₃ (30% by weight) up tobasic pH. The white solid obtained is dissolved in dichloromethane. Theaqueous phase is separated then the organic phase is dried on MgSO₄,filtered and concentrated to yield a white solid (yield>90%). δ_(H) (300MHz, CDCl₃) 1.4 (t; J 7.2; 6H), 4.34 (q; J 7.2; 4H), 7.63 (d; J 8.7;4H), 7.83 (d; J 8.7; 4H).

EXAMPLE 30 Synthesis of 4-(1-oxo-4-methyl-pentyl)bromobenzene⁽⁹⁾ (WP132)

A mixture of 4-methyl valeric acid (15 g, 129.1 mmol) and thionylchloride (10.8 ml, 148 mmol) is heated at reflux for 90 minutes. Theexcess thionyl chloride is distilled under reduced pressure, then theresidue is taken up in 48 ml of bromobenzene. After cooling to 0° C.,anhydrous aluminum chloride (13.8 g, 103.5 mmol) is added to thesolution. The mixture is stirred at ambient temperature for 80 hours,then treated with the addition of iced water, then with 20 ml ofconcentrated HCl. The organic phase is separated and the aqueous phaseextracted by Et₂O. The recombined organic phases are washed successivelywith water then with a solution saturated with sodium chloride, dried onMgSO₄, filtered and concentrated under reduced pressure. The residue ispurified either by a) distillation (approximately 80° C./0.01 mm) or b)chromatography on a silica gel (pentane 100% then pentane/ethyl acetate10/1) followed by filtration, water wash and drying, to yield 20.337 g(62%, not optimized) of a colorless solid. Analyses identical to theliterature.

EXAMPLE 31 Synthesis of 4-(1,1,4-trimethyl-pentyl)bromobenzene⁽¹⁰⁾(WP133)

A 2 M solution of trimethylaluminum in hexane (10.5 ml, 2 eq) is slowlyadded to a solution of ketone WP132 prepared according to example 30(2.675 g, 10.49 mmol) in chlorobenzene (4 ml) and water (100 μl) under anitrogen atmosphere and cooled to 0° C. The hexane is then distilled andthen the solution is heated at reflux for 80 hours. After cooling, themixture is treated with the slow addition of water, then with 2 N HCland is heated until the salts are dissolved. After cooling, the mixtureis extracted several times with Et₂O. The recombined organic phases arewashed successively with water then with a solution saturated with NaCl,dried on magnesium sulfate, filtered and concentrated under reducedpressure. The residue is then distilled (approximately 100° C./0.16 mm)to yield a mixture of products which is dissolved in 10 ml ofdichloromethane, treated with 1.0 g of M-CPBA and stirred for 12 hours.After concentration under reduced pressure, the residue is purified bychromatography on a silica gel (pentane 100%) to yield 1.143 g (40%, notoptimized) of a colorless liquid. Analyses identical to the literature.

EXAMPLE 32 Synthesis of Bis-Amidrazone (WP134)

Hydrazine monohydrate (637 μl, 13.1 mmol) is added over the course of 10minutes to a suspension of WP129 prepared according to example 29 (1.296g, 4.37 mmol) in absolute ethanol (7 ml). After 24 hours of stirring,the precipitate is filtered, washed successively with ethanol then withdiethyl ether and is dried to yield 1.077 g (92%) of a yellow solid.δ_(H) (300 MHz, DMSO) 5.00 (brs; 4H), 5.62 (s; 4H), 7.66 (d; J 8.7; 4H),7.78 (d; J 8.7; 4H); MS (Electrospray) m/z 269 (MH⁺, 100%).

EXAMPLE 33 Synthesis of1,4-bis[5,6-(4,4′-diphenyl-1,2,4-triazine-3-yl]diphenyl (WP135)

WP134 prepared according to example 32 (300 mg, 1.12 mmol) is added allat once to a solution of benzyl (589 mg, 2.79 mmol) in ethanol (20 ml).The mixture is heated at reflux for 15 hours. After returning to ambienttemperature, the precipitate obtained is filtered, washed successivelywith ethanol then with diethyl ether and is dried to yield 548 mg (80%)of a yellow solid. δ_(H) (300 MHz, DMSO-d, 120° C.) 7.40-7.57 (m; 12H),7.60 (m; 4H), 7.68 (m; 4H), 8.10 (d; 4H), 8.77 (d; 4H). MS(Electrospray) m/z 617 (MH⁺, 10%), 457 (26%), 190 (100%).

EXAMPLE 34 Synthesis of1,2-bis-[4(2-ethyl-hexyloxy)-phenyl]-ethane-1,2-dione (WP141)

Soda (1.24 g, 30.8 mmol) is added to a solution of WP32 preparedaccording to example 5 (3.00 g, 12.4 mmol) in DMF (75 ml). The mixtureis stirred for 5 minutes at ambient temperature, then 2-ethylhexylbromide (6.6 ml, 37.1 mmol) is added over the course of 1 minute. After60 hours of stirring at 60° C., the mixture is cooled. The mixture ispoured into iced water and extracted by ethyl acetate. The organic phaseis washed several times with a solution saturated with sodiumbicarbonate, dried on sodium sulfate, filtered and concentrated. Theresidue is purified by flash chromatography on a silica gel (pentane100% then pentane/ethyl acetate 23/1) to yield 4.879 g (85%) of a yellowliquid. δ_(H) (300 MHz, CDCl₃) 0.90 (m; 12H), 1.25-1.35 (m; 8H), 1.45(m; 8H), 1.75 (m; 2H), 3.91 (d; J 6.0; 4H), 6.94 (d; J 9.0; 4H), 7.92(d; J 9.0; 4H); MS (Electrospray) m/z 954 (2M+H⁺, 100%), 467 (MH⁺, 33%).

EXAMPLE 35 Synthesis of1,4-bis[5,6-bis(4,2-ethylhexyloxyphenyl)-1,2,4-triazine-3-yl]benzene(WP144)

Terephthalamidrazone WP29 prepared according to example 3 (300 mg, 1.56mmol) is added all at once to a solution of WP141 prepared according toexample 34 (1.821 g, 1.52 mmol) in ethanol (40 ml). The mixture isheated at reflux for 15 hours. After returning to ambient temperature,the precipitate obtained is filtered, washed successively with ethanolthen with diethyl ether and is dried to yield 1.452 g (88%) of a yellowsolid. δ_(H) (300 MHz, CDCl₃) 0.90 (m; 24H), 1.25-1.60 (m; 32H), 1.74(m; 4H), 3.89 (d; J 6.0; 8H), 6.92 (m; 8H), 7.63 (d; J 8.4; 4H), 7.74(d; J 8.4; 4H), 8.82 (s; 4H); MS (Electrospray) m/z 1053 (MH⁺, 100%).

EXAMPLE 36 Synthesis of1,2-bis-[4-(1-methyl-heptyloxy)-phenyl]-ethane-1,2-dione (WP145)

Potassium carbonate (900 mg, 7.1 mmol) and then (S)-2-octyl tosylate⁽¹⁰⁾(740 mg, 2,6 mmol) are added to a solution of WP32 prepared according toexample 5 (286 mg, 1.184 mmol) in DMF (6 ml). After 15 hours of stirringat 50° C., the mixture is cooled then poured into iced water andextracted by ethyl acetate. The organic phase is washed several timeswith a solution saturated with sodium bicarbonate, dried on sodiumsulfate, filtered and concentrated. The residue is purified by flashchromatography on a silica gel (pentane 100% then pentane/ethyl acetate20/1) to yield 406 mg (74%) of a yellow oil. δ_(H) (300 MHz, CDCl₃)0.80-0.93 (m; 6H), 1.20-1.40 (m; 12H), 1.31 (d; J 6; 6H), 1.55 (m; 4H),1.73 (m; 4H), 4.46 (m; 2H), 6.91 (d; J 9.3; 4H), 7.92 (d; J 9.3; 4H); MS(Electrospray) m/z 955 (2M+Na⁺, 100%), 467 (MH⁺, 56%).

EXAMPLE 37 Synthesis of1,4-bis[5,6-bis(4,1-methylheptyloxyphenyl)-1,2,4-triazine-3-yl]benzene(WP149)

Terephthalamidrazone WP29 prepared according to example 3 (69 mg, 0.355mmol) is added all at once to a solution of WP145 prepared according toexample 36 (398 mg, 0.85 mmol) in ethanol (8 ml). The mixture is heatedat reflux for 15 hours. After returning to ambient temperature, theprecipitate obtained is filtered, washed successively with ethanol thenwith cold pentane and dried to yield a yellow solid (yield notcalculated). δ_(H) (300 MHz, CDCl₃) 0.80-0.95 (m; 12H), 1.20-1.53 (m;24H), 1.31 (d; J 6; 12H), 1.60 (m; 8H), 1.75 (m; 8H), 4.42 (m; 4H), 6.88(d; J 9.0; 4H), 6.91 (d; J 9.0; 4H), 7.63 (d; J 9.0; 4H), 7.73 (d; J9.0; 4H), 8.82 (s; 4H); MS (Electrospray) m/z 1053 (MH⁺, 100%).

EXAMPLE 38 Synthesis of1,2-bis-[4-(1,1,4-trimethyl-pentyl)-phenyl]-ethane-1,2-dione (WP150)

A solution of s-BuLi (1.3 M in cyclohexane, 2.9 ml, 3.71 mmol) is addedslowly to a solution of WP133 prepared according to example 31 (1.0 g,3.71 mmol) in anhydrous THF (4.6 ml) at −78° C. and under a nitrogenatmosphere. After 1 hour of stirring during which 3 additional ml of THFare added, the mixture is heated to approximately 0° C. then transferredusing a cannula to a suspension of 1,4-dimethylpiperazine-2,3-dione (240mg, 1.688 mmol) in THF (6 ml) cooled to 0° C. After returning to ambienttemperature, the mixture is stirred for 3 hours then treated with 2 NHCl. After dilution with Et₂O, the organic phase is separated and theaqueous phase is extracted twice with Et₂O. The recombined organicphases are washed with water and then with a solution saturated withNaCl and are dried on magnesium sulfate. After filtration andconcentration, the residue is purified by flash chromatography on asilica gel (pentane/ethyl acetate 100/0; 6/1; 4/1) to yield 523 mg (71%,not optimized) of a yellow oil. δ_(H) (300 MHz, CDCl₃) 0.80 (d; J 6.0;12H), 0.85-0.97 (m; 4H), 1.3 (s; 12H), 1.40 (sept.; J 6.0; 2H),1.55-1.70 (m; 4H), 7.45 (d; J 8.7; 4H), 7.91 (d; J 8.7; 4H).

EXAMPLE 39 Synthesis ofbis(4-(1,1,4-trimethylpentyl)phenyl)-1,2,4-triazine-3-yl]benzene (WP151)

Terephthalamidrazone (104 mg, 0.544 mmol) is added all at once to asolution of WP150 prepared according to example 38 (520 mg, 1.196 mmol)in ethanol (10 ml). The mixture is heated at reflux for 15 hours. Afterreturning to ambient temperature, the precipitate obtained is filtered,washed with ethanol and dried to yield 348 mg (65%, not optimized) of ayellow solid. δ_(H) (300 MHz, CDCl₃) 0.81 (d; J 6.0; 24H), 0.90-0.10 (m;8H), 1.31 (s; 24H), 1.40 (sept.; J 6.0; 4H), 1.53-1.70 (m; 8H), 7.33 (d;J 8.7; 4H), 7.34 (d; J 8.7; 4H), 7.58 (d; J 8.7; 4H), 7.66 (d; J 8.7;4H); MS (Electrospray) m/z 1978 (2M+H⁺, 30%), 989 (MH⁺, 100%).

BIBLIOGRAPHICAL REFERENCES FOR SYNTHESES

-   ⁽¹⁾ G. Pitet, H. Cousse, G. Mouzin, Boll. Chim. Farm., 1980, 119,    469-   ⁽²⁾ F. Lu, Y. Wang, L. Xing, Gaofenzi Tongxun, 1981, 5, 319-   ⁽³⁾ X. Yi, G. Wu, F. Lu, A. Tang, J. Appl. Polym. Sci., 2001, 907,    82-   ⁽⁴⁾ H. Simbürger, W. Kern, K. Hummel, C. Hagg, Polym., 2000, 41,    7883-   ⁽⁵⁾ L. Brunsvelt, H. Zhang, M. Glasbeek, A. J. M. Vekemans, E. W.    Meijer, J. Am. Chem. Soc., 2000, 122, 6175-   ⁽⁶⁾ T. Tagusari, Y. Honda, Jpn. Kokai Tokkyo Koho, 1992, JP 04279546-   ⁽⁷⁾ M. Wehmeier, M. Wagner, K. Mullen, Chem. Eur. J., 2001, 7, 2197-   ⁽⁸⁾ T. Shono, M. Masahiro, S. Matsumura, N. Asano, Jpn. Tokkyo Koho,    1968, JP 43015992-   ⁽⁹⁾ U.S. Pat. No. 5,202,471, 1993-   ⁽¹⁰⁾ M. S. Alnajjar, H. G. Kuivila, J. Am. Chem. Soc., 1985, 107,    422.

Below are found the physicochemical studies carried out on the compoundswhich are objects of the present invention, in comparison with thefollowing commercial filters:

EXAMPLE 40 Spectral Characteristics of the Products Molar ExtinctionCoefficient and Specific Absorbance

The calculation of the molar extinction coefficient (ε) is made from theBeer-Lambert law:

${{Log}_{10}( \frac{I_{0}}{I} )} = {{ɛ \cdot l \cdot c} = A}$Wherein:

-   A=absorbance-   I₀=intensity of the incident light-   I=intensity of the transmitted light-   ε=molar extinction (or molar absorbance) coefficient in M⁻¹ cm⁻¹-   l=path length in cm-   c=concentration in mol/l

The molar extinction coefficient can be expressed with respect to agiven mass of the product. It thus makes it possible to be able tocompare the coefficients of extinction between products for the samegiven quantity. This quantity is 1% by weight. The molar extinctioncoefficient thus becomes the specific absorbance (A_(1cm) ^(1%)).

It is expressed as follows:

$A_{1\mspace{11mu}{cm}}^{1\%} = {ɛ \cdot \frac{10}{M}}$Wherein:

-   A_(1cm) ^(1%)=specific absorbance-   ε=molar extinction coefficient-   M=molar mass

The spectral characteristics of the compounds in comparison withcommercial filters at a concentration of 10 μg/ml are summarized intables 2-1 and 2-2.

Procedure: The products are dissolved in ethyl acetate to aconcentration of 10 μg/ml. The spectra are measured using a dual-beamspectrophotometer (Varian CARY 50 Scan) between 290 nm and 400 nm.

TABLE 2-1 Maximum molar extinction coefficient Maximum specificabsorbance Molecules UVC UVB UVA Visible UVC UVB UVA Visible PARSOL 8633at 34100 278 at 1100 1789 ® 275 at 360 275 at 360 PARSOL 24600 848 MCX ®at 310 at 310 TINOSORB 41750 49580 751 789 S ® at 310 at 345 at 310 at345 TINOSORB 36600 36400 556 552 M ® at 305 at 345 at 305 at 345

TABLE 2-2 Compounds of formula (I) Maximum molar Maximum specificextinction coefficient absorbance Molecules UVC UVB UVA Visible UVC UVBUVA Visible WP30 50200 928 at 325 at 325 WP35 29600 27800 490 460 at 310at 355 at 310 at 355 WP39 48200 808 at 335 at 335 WP41 72000 91400 527669 at 305 at 330 at 305 at 330 WP52 57300 669 at 330 at 330 WP76 54000998 at 290 at 290 WP89 47700 778 at 330 at 330 WP96 56000 638 at 335 at335 WP100 43400 640 at 300 at 100 WP104 90000 1176 at 300 at 300 WP10792000 95000 757 783 at 300 at 335 at 300 at 335 WP135 57000 924 at 330at 330 WP144 66000 64000 626 at 315 607 at 315 at 355 at 355 WP149 5600059000 532 at 315 560 at 315 at 355 at 355 WP151 60500 611 at 340 at 340

EXAMPLE 41

The products tested are classified according to spectral distribution inUVA and UVB in a range from 290 nm to 400 nm. It is possible todifferentiate them according to their spectral distribution:

Products with a narrow spectrum:

-   -   Products absorbing in the range between 280 nm and 320 nm (UVB)    -   Products absorbing in the range between 320 nm and 400 nm (UVA)

Products with a broad spectrum:

-   -   Products absorbing in UVB (280-320 nm) and UVA-II (380-360 nm)    -   Products covering UVB and UVA (280-400 nm).

EXAMPLE 41-1 Spectral Distribution of Compounds of Formula (I)

WP89, WP96, WP100, WP104, WP107, WP135, WP144, WP149, WP151, WP35, WP39,WP41, WP52 and WP30 absorb in UVB and UVA (see FIGS. 1 and 2).

WP76 absorbs in UVB (see FIG. 3).

EXAMPLE 41-2

Table 3 summarizes the spectral distributions of the compounds tested.

TABLE 3 Molecules UVB 280-320 nm UVA-II 320-340 nm UVA-I 340-400 nmAbsorption peaks(nm) Parsol 1789 ®

360 WP76 

290 Parsol ® 310 Tinosorb S ® 310 and 345 Tinosorb M ® 305 and 345 WP30 325 WP35 

355 WP39 

335 WP41  205 and 330 WP52 

330 WP89 

330 WP96 

335 WP100

300 WP104

300 WP107

300 and 335 WP135

330 WP144 315 and 355 WP149 315 and 355 WP151

340 Very strong absorption

Strong absorption

Average absorption

Weak absorptoin No absorption

EXAMPLE 42 Evaluation of Sun Protection Factor (SPF) In Vitro in aChemical Solvent

The in vitro methods of determining the protective effectiveness of sunproducts consist of measuring by transmission spectrophotometry theabsorption spectrum of the filter in solution or of the product appliedon a substrate with the aim of simulating the surface of the skin. Theeffectiveness against UVB and/or UVA rays, or the effect on thecutaneous response, are then determined by calculation, taking intoaccount or not the UV radiation action spectrum for the damageconsidered.

The Sayre/Agin and Diffey/Robson method, used since the 1990s, involvesa comparative measurement, with the aid of an integrating-spherespectroradiometer, of the transition from 290 nm to 400 nm in 5 nmsteps, the sample being subjected to UV radiation from a stable knownsource covering the whole of the UV spectrum (unfiltered xenon).

Diffey and Robson evaluate the erythemal response by the followingcalculation:

${FPS} = \frac{( {\sum\limits_{290}^{400}{{E(\lambda)}*ɛ}} )}{( {\sum\limits_{290}^{400}\frac{{E(\lambda)}*ɛ}{\overset{\_}{FPM}(\lambda)}} )}$E(λ)=spectral irradiation in W(m-²) (nm⁻¹) at 40° N sun at 20° zenithangle

-   ε=erythematous capacity

${\overset{\_}{FPM}(\lambda)} = \frac{( {\sum\limits_{i = 1}^{N}{{{FPM}(\lambda)}i}} )}{N(\lambda)}$N(λ)=number of values for a given wavelength

The Diffey and Robson formula makes it possible to determine SPF fromthe measurement of transmittance between 290 nm and 400 nm.Transmittance is measured in solution in ethyl acetate at aconcentration of 10 μg/ml using a UV-visible spectrophotometer (VarianCARY 50 Scan).

${{FPM}(\lambda)} = \frac{1}{T(\lambda)}$T(λ)=transmittance at wavelength λ

The results of the measurements taken are summarized in table 5.

TABLE 4 In vitro SPF measurement in a chemical solvent Molecules SPFParsol MCX ® 20.78 Parsol 1789 ® 51.1 Tinosorb M ® 54.07 Tinosorb S ®76.19 Compounds of formula (I) WP96 68.02 WP104 79.35 WP149 74.1 WP15167.2

EXAMPLE 43 Study of Photostability in Solution in a Chemical Solvent

A Suntest CPS+(Atlas, Linsengenicht/Altenhasslan, Germany) was used. TheSuntest makes it possible to reproduce the solar spectrum and thus tocarry out exposures inside at any time without weather constraints.

Setting the MED (Minimal Erythemal Dose):

The radiance of the solar simulator was carefully measured with aspectroradiometer (MSS 2044, Bielefeld, Germany). UVB and UVAintensities were 0.49 mW/cm² and 6.32 mW/cm², respectively. The MEDvalue defined by COLIPA is 5.6 J/cm² in total UV (22). The UV total(UVA+UVB) accounts for 14.8% of the energy delivered by the lamp (power460 W/m²). An irradiation dose equivalent to 1 MED corresponds to 37.83J/cm² (in total spectrum) delivered by the lamp.

The Suntest test duration is calculated using the following formula:t=H/Ewith:

-   E=illumination energy in W/m²-   H=irradiation dose in J/m²-   t=duration of the test in s

The setting of the MED on the Suntest and the correspondence with sunintensity at 3 seaside resorts are indicated in table 6.

TABLE 6 Sun intensity Extreme Intense Average Location (June 21) AgadirToulon La Baule Number of MED/d    20    10    5 Dose of correspondingirradiation 7566000 3783000 1891500 on the Suntest (in J/m²) Testduration 4 h 2 h 1 h 34 min 17 min 8 minProcedure:

The solutions of the compounds are prepared at a concentration of 500μg/ml in methanol. 50 μl (25 μg) of each solution are deposited in acrystallizer, then irradiated in the Suntest at 5, 10 and/or 20 MED. Anon-irradiated control is prepared (deposit of 50 μl of solution andaddition of 2.450 ml of methanol). The solvent evaporates duringirradiation and the products are taken up in 2.5 ml of methanol. Afterirradiation, the absorbance of each solution is measured with theUV-visible spectrophotometer (Varian CARY 50 Scan).

The photostability measurement results for the compounds of formula (I)are summarized in table 7.

TABLE 7 Photostability at 5 MED Photostability at 10 MED relativerelative standard standard standard standard molecule mean deviationdeviation mean deviation deviation WP30 77.75 0.78 1.00% 56.12 0.54137.83% WP76 69.23 1.31 1.89% 62.53 0.91 137.39% WP96 83.30 5.94 7.13%74.35 4.15 138.07% WP104 93.70 4.24 4.53% 88.55 2.97 138.43% WP107 89.271.46 1.64% 84.75 1.02 138.29% WP135 57.45 1.63 2.83% 33.66 1.13 136.58%WP149 80.40 1.56 1.93% 38.16 1.09 137.95% WP151 76.16 4.30 5.64% 70.153.00 137.76%

EXAMPLE 44 Solubility Study

The solubility results for solvents or excipients used in cosmetics aresummarized in table 8.

TABLE 8 Compounds of formula (I) Molecules Excipients Solubility (%)WP96 Myritol 318 ® 0.1 Finsol V NT ® 1 PEG400 ® 2 WP107 Finsol V NT ® 1PEG400 ® 1 Arlasolve DMI ® 1 WP149 Myritol 318 ® 2.5 Finsol V NT ® 4.5Isopropyl adipate 2 WP151 Myritol 331 ® 2 Finsol V NT ® 5 Isopropyladipate 1 PEG400 ® 0.5 Arlasolve DMI ® = dimethyl isosorbide Finsol VNT ® = C₁₂-C₁₅ alkyl benzoate Myritol 318 ® = caprylic/caprictriglycerides Myritol 331 ® = cocoglycerides (glyceryl esters andderivatives) PEG400 ® = polyethylene glycol (n = 400)

TABLE 9 Compounds of formula (I) Solubilities Molecules SolubleInsoluble WP30 DMSO or hot DMF Water Ethyl acetate (PS) MeOH CHCl₃Acetone Acetonitrile Benzene Myritol Transcutol WP35 DMSO 3.5% MeOHTranscutol 0.5% CHCl₃ Ethyl acetate Hexane Myritol WP38 Benzene MeOHToluene DMC Myritol AcOEt Transcutol WP39 DMSO or hot DMF Water MeOHCHCl₃ Acetone Acetonitrile Benzene WP40 DMSO or hot DMF Water MeOH CHCl₃Acetone Acetonitrile Benzene WP41 DMC EtOH AcOEt (PS) Hexane MeOH (PS)Myritol DMSO 2.7% Transcutol 0.1% WP52 DMSO or hot DMF Water MeOH CHCl₃Acetone Acetonitrile Benzene Myritol Transcutol WP76 DMSO or hot DMFWater MeOH CHCl₃ Acetone Acetonitrile Benzene WP89 Ethyl acetate WP96DMC EtOH CHCl₃ Myritol Et₂O Acetic acid Toluene Octanol Transcutol 0.5%Methanol WP100 Hot DMSO DCM Et₂O Toluene Octanol EtOH Myritol TranscutolWP104 DCM EtOH CHCl₃ MeOH Toluene 1-Octanol DMSO Acetic acid Ethylacetate Myritol Transcutol WP107 DCM EtOH CHCl₃ Acetic acid Toluene MeOHOctanol Myritol Ethyl acetate Transcutol DMSO DMSO: dimethylsulfoxideDMF: dimethylformamide DCM: dichloromethane

EXAMPLE 45 Formulation Example

Composition (H/E emulsion) Quantity (g) Hydrated magnesium sulfate 0.7Ethyl hexyl para methoxy cinnamate 5 WP151 5 C₁₂-C₁₅ alcohol benzoate 10Titanium oxide 3 Triethanolamine Qs pH 7 Glyceride 3 Preservatives QsDemineralized water qsp 100

1. 5,6-diphenyl-1,2,4-triazinic compound of general formula (I):

wherein: R₁, R₂, R₃ and R₄, identical or different, represent ahydrogen, fluorine, chlorine or bromine atom, a C₁ to C₁₂ linear orbranched alkyl group, a hydroxy group, a C₁ to C₁₈ linear or branchedalkoxy group, a poly(ethoxy)-alkoxy group with a C₁ to C₄ alkyl fragmentand an ethoxy number ranging from 1 to 4, an amino group, or a mono- ordi-alkylamino group with a C₁ to C₄ alkyl fragment, X represents anortho-, meta- or para-phenylene group, a 4,4′-biphenylene group, a 2,4-or 2,6- or 3,4- or 3,5-pyridinylene group, a 2,2′-bipyridinylene group,a meta- or para-phenylenediamino group, an ethylenediamino group, a2,2′-piperazinylene group, a diacyl group of formula —(R₄CO)₂— whereinR₄ represents a phenyl radical, an alkylated chain of 3 to 10 carbonatoms, a phenanthrenylene group or an anthracenylene group, with theexception of 1,4-bis(5,6-diphenyl-1,2,4-triazin-3-yl)benzene,2,4-bis(5,6-diphenyl-1,2,4-triazin-3-yl)pyridine, and2,6-bis(5,6-diphenyl-1,2,4-triazin-3-yl)pyridine. 2.5,6-diphenyl-1,2,4-triazinic compound of formula (I) according to claim1, wherein: R₁, R₂, R₃ and R₄ represent a C₁ to C₁₂ linear or branchedalkyl group located in the para position, or a C₁ to C₁₈ linear orbranched alkoxy group located in the para position, and X represents a4,4′-biphenylene group.
 3. 5,6-diphenyl-1,2,4-triazinic compoundaccording to claim 1, selected from the group consisting of: WP35:1,4-Bis[5,6-(4,4′-dihydroxy)-diphenyl-1,2,4-triazin-3-yl]benzene WP38:1,4-Bis[5,6-(4,4′-di-octadecyloxy)-diphenyl-1,2,4-triazin-3-yl]benzeneWP39: 1,4-Bis[5,6-(4,4′-dimethyl)-diphenyl-1,2,4-triazin-3-yl]benzeneWP40: 1,4-Bis[5,6-(4,4′-dimethoxy)-diphenyl-1,2,4-triazin-3-yl]benzeneWP41:1,4-Bis[5,6-(4,4′-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-)-diphenyl-1,2,4-triazin-3-yl]benzene WP52:1,4-Bis-[5,6-(4,4′-dibromo)-diphenyl-1,2,4-triazin-3-yl]benzene WP76:1,3-Bis(5,6-diphenyl-1,2,4-triazin-3-yl)benzene WP89:1,4-Bis[5,6-(4,4′-difluoro)-diphenyl-1,2,4-triazin-3-yl]benzene WP96:1,4-Bis[5,6-(4,4′-dihexyl)-diphenyl-1,2,4-triazin-3-yl]benzene WP100:1,4-Bis[5,6-(4,4′-dichloro)-diphenyl-1,2,4-triazin-3-yl]benzene WP104:1,4-Bis[5,6-(4,4′-4-di-tert-butyl)-diphenyl-1,2,4-triazin-3-yl]benzeneWP107: 1,4-Bis[5,6-bis(4-dodecylphenyl)-1,2,4-triazine-3-yl]benzeneWP135: 1,4-bis-[5,6-(4,4′-diphenyl-1,2,4-triazine-3-yl]diphenyl WP144:1,4-bis-[5,6-bis(4,2-ethylhexyloxyphenyl)-1,2,4-triazine-3-yl]benzeneWP149:1,4-bis[5,6-bis(4,1-methylheptyloxyphenyl)-1,2,4-triazine-3-yl]benzeneWP151: bis(4-(1,1,4-trimethylpentyl)phenyl)-1,2,4-triazine-3-yl]benzene.4. A cosmetic sunscreen composition active in UV-A and/or UV-B and/orUV-C containing an effective quantity of one or more5,6-diphenyl-1,2,4-triazinic compound of formula (I):

wherein: R₁, R₂, R₃ and R₄, identical or different, represent ahydrogen, fluorine, chlorine or bromine atom, a C₁ to C₁₂ linear orbranched alkyl group, a hydroxy group, a C₁ to C₁₈ linear or branchedalkoxy group, a poly(ethoxy)-alkoxy group with a C₁ to C₄ alkyl fragmentand an ethoxy number ranging from 1 to 4, an amino group, or a mono- ordi-alkylamino group with a C₁ to C₄ alkyl fragment, X represents anortho-, meta- or para-phenylene group, a 4,4′-biphenylene group, a 2,4-or 2,6- or 3,4- or 3,5-pyridinylene group, a 2,2′-bipyridinylene group,a meta- or para-phenylenediamino group, an ethylenediamino group, a2,2′-piperazinylene group, a diacyl group of formula —(R₄CO)₂— whereinR₄ represents a phenyl radical, an alkylated chain of 3 to 10 carbonatoms, a phenanthrenylene group or an anthracenylene group incombination with a cosmetically acceptable excipient.
 5. A cosmeticsunscreen composition according to claim 4, wherein containing inaddition one or more sun filters active in UV-A and/or UV-B and/or UV-C.6. A sun filter active in UV-A and/or UV-B and/or UV-C for human skinand/or hair, containing one or more 5,6-diphenyl-1,2,4-triaziniccompound of general formula (I):

wherein: R₁, R₂, R₃ and R₄, identical or different, represent ahydrogen, fluorine, chlorine or bromine atom, a C₁ to C₁₂ linear orbranched alkyl group, a hydroxy group, a C₁ to C₁₈ linear or branchedalkoxy group, a poly(ethoxy)-alkoxy group with a C₁ to C₄ alkyl fragmentand an ethoxy number ranging from 1 to 4, an amino group, or a mono- ordi-alkylamino group with a C₁ to C₄ alkyl fragment, X represents anortho-, meta- or para-phenylene group, a 4,4′-biphenylene group, a 2,4-or 2,6- or 3,4- or 3,5-pyridinylene group, a 2,2′-bipyridinylene group,a meta- or para-phenylenediamino group, an ethylenediamino group, a2,2′-piperazinylene group, a diacyl group of formula —(R₄CO)₂— whereinR₄ represents a phenyl radical, an alkylated chain of 3 to 10 carbonatoms, a phenanthrenylene group or an anthracenylene group.
 7. Alight-protective agent active in UV-A and/or UV-B and/or UV-C, useful inthe synthetic materials industry, containing one or more5,6-diphenyl-1,2,4-triazinic compound of formula (I) as defined in claim6.
 8. The light-protective agent according to claim 7 aslight-protective agents incorporated into the composition of plastics,glass or textiles.
 9. A cosmetic sunscreen composition according toclaim 4, wherein the effective quantity of the one or more5,6-diphenyl-1, 2, 4-triazinic compound of formula (I) is comprised ofbetween 0.1% and 20% by weight with respect to the total weight of thecomposition.
 10. A cosmetic sunscreen composition according to claim 4,wherein the one or more 5,6-diphenyl-1,2,4-triazinic compound of formula(I) comprises 1,4-bis(5,6-diphenyl-1,2,4-triazin-3-yl) benzene.
 11. Asun filter according to claim 6, wherein the one or more5,6-diphenyl-1,2,4-triazinic compound of formula (I) comprises1,4-bis(5,6-diphenyl-1,2,4-triazin-3-yl)benzene.
 12. A light-protectiveagent according to claim 7, wherein the one or more 5,6-diphenyl-1,2,4-triazinic compound of formula (I) comprises 1,4-bis(5,6-diphenyl-1,2,4-triazin-3-yl)benzene.